Tuberculosis (TB) is a disease caused by infection with the slow-growing bacteria Mycobacterium tuberculosis (Mtb). TB can be either latent or active, the latter meaning that the bacteria are growing and causing symptoms. Most often, the bacteria are found in the lungs, which is called pulmonary TB, and which is contagious. Approximately a third of the world population is infected with Mtb and 5-10% of these individuals will develop active TB in the course of their lives. TB is responsible for more than two million deaths each year, with more than 90% of cases occurring in developing countries.
Current treatment of drug-susceptible TB typically consists of a cocktail of antibiotic drugs taken over a period of six months to one year or more for antibiotic-resistant strains as recommended by the World Health Organization (WHO). Even though a large proportion of actively replicating bacilli are killed within the first month of therapy, the remaining duration of treatment is required for the killing of slow-growing persisting Mtb bacteria that are primarily located inside cells, in order to prevent relapse of the disease. Discontinuation of therapy earlier than the six-month duration recommended by the WHO will result in relapse of disease due to the multiplication of the remaining bacteria, whereas strict adherence to the six-month therapy can result in cure rates of only over 90% under optimal circumstances.
However, there are several disadvantages of such lengthy treatment regimes. Indeed, the actual cure rate in many developing countries are below the 85% target cure rate set by the WHO, at times dipping below 50%. The low treatment success rate is attributed to poor patient compliance resulting in relapses in the form of multidrug and extremely drug-resistant TB (MDR-TB/XDR-TB). Therefore, adhering to all doses of the antibiotics is very important, and daily visits with a health professional observing the intake of the medicine(s) are involved to ensure patient compliance. This is known as directly observed therapy (DOT), which entails a high cost and logistical burden.
Despite the success of TB drug therapy in saving the lives of many since it was first introduced, the emergence of MDR and XDR-TB highlights the inherent limitations in the usage of antibiotics against bacteria.
Thus, there is still an urgent need for improved therapy against active TB in order to curb the current global TB epidemic.
One way of shortening the duration of the treatment of TB has been described in WO 2004/062607, and includes the use of weak acids or their precursors for the treatment of TB.
An alternative and independent route to fight TB is by vaccination. However, this approach generally aims at preventing TB, by inducing immune responses in people that do not have active TB (and preferably are not even infected with Mtb when vaccinated), and thus the vaccines in this approach are prophylactic vaccines. Bacille Calmette-Guérin (BCG), a live and attenuated strain of Mycobacterium bovis, is the only available vaccine against TB to date and has been used for the vaccination of newborns for decades. This vaccine has its limitations however, and progress in generating more effective TB vaccines has been made with several candidate vaccines in recent years. One candidate that has been in clinical trials is based on adenovirus serotype 35 expressing Ag85A, Ag85B and TB10.4 antigens of Mtb (Havenga et al., 2006; Rado{hacek over (s)}evié et al., 2007; WO 2006/053871). This vaccine has been demonstrated to be safe in uninfected people and was able to induce high T-cell responses against Mtb antigens of the vaccine, making it a promising candidate for a prophylactic TB vaccine.
Vaccination in patients having active TB with the aim of treating these patients would, however, require a therapeutic TB vaccine. In principle, such a therapeutic TB vaccine might have the potential to improve therapy for active TB.
The concept of a therapeutic TB vaccine to cure tuberculosis was first coined by Robert Koch himself in 1890 when he announced the cure of tuberculosis by tuberculin therapy (see Burke, 1993). Tuberculin consists of extracts of Mtb.
However, although the treatment succeeded in curing the disease in some patients, a subset of patients exhibited worsening of symptoms, which became known as Koch's phenomenon. Koch's phenomenon occurs due to systemic release of Th1-associated cytokines, resulting in necrosis of TB lesions (Churchyard et al., 2009) that could lead to devastating clinical symptoms, which may even result in death. Thus, an important safety consideration that will need to be demonstrated for any new therapeutic TB vaccine candidate is the absence of Koch's phenomenon following widespread vaccine administration to TB patients. This can only be addressed by well-designed, controlled clinical trials in endemic areas.
In recent times, interest in reinvigorating therapeutic TB vaccination regained attention, particularly with the possibility for use as an adjunct to TB chemotherapy with the hope of shortening treatment. Animal studies have indicated that DNA vaccines encoding TB antigens such as heat shock protein 65 (HSP-65) (Lowrie et al., 1999), Ag85A (Ha et al., 2005) and Ag85B (Zhu et al., 2005) could reduce bacterial burden in Mtb-infected animals (Ha et al., 2005; Zhu et al., 2005), and prevent relapses when used in conjunction (Ha et al., 2005) or following the completion of chemotherapy (Lowrie et al., 1999).
A therapeutic TB vaccine, given when the bacterial burden is low, early in chemotherapy, should enable the immune system to target persisters, to result in the prevention of relapse. In clinical studies, a heat-killed environmental mycobacterial (Mycobacterium vaccae) preparation has been shown to be effective as an adjunctive treatment in MDR-TB as shown in trials conducted in China (Fan et al., 2007). This therapy relies on the non-specific nature of M. vaccae immunomodulation. Another vaccine in clinical development is RUTI, which is a liposome preparation containing cell wall of Mtb, aimed for usage as an adjunct to TB chemotherapy (Churchyard et al., 2009).
Despite the progress, an important safety consideration that still remains to be demonstrated for these vaccines is the absence of Koch's phenomenon following widespread vaccine administration to TB-infected patients, an important aspect that can only be addressed by well-designed, controlled clinical trials in endemic areas. Indeed, a few years ago it was reported in a conference by one company active in this field that development of a therapeutic vaccine candidate had to be discontinued for safety reasons. Furthermore, although some reports for treatment of TB using a DNA vaccine encoding hsp60 or Ag85 antigen in mice were successful, others reported classical Koch reactions in an immunotherapeutic mouse model (Taylor et al., 2003). This underscores the risk of eliciting Koch's phenomenon by immunotherapeutic vaccination, and thus highlights the need for clinical studies for each vaccine candidate to assess potential safety problems.
US 2004/0057963 relates to therapeutic vaccines against latent TB by delivering polypeptides or nucleic acids encoding such, which polypeptides are upregulated or expressed during the latent stage of mycobacteria infection. US 2004/0057963 teaches that some antigens (exemplified therein by ESAT6), though potent as prophylactic vaccine, have no effects as therapeutic vaccines, whereas, in contrast with other antigens (exemplified therein by Rv2031c), can be efficient therapeutic vaccines although they have no or only negligible effects as prophylactic vaccines (see, e.g., Example 2 therein). Thus, the skilled person consulting US 2004/0057963 is taught to use different antigens for therapeutic TB vaccines than for prophylactic TB vaccines.
A further complicating factor for therapeutic vaccination of patients with active TB, is that individuals with active TB actually possess T lymphocytes that are unresponsive to stimuli with antigens from Mtb, as observed by tetramer binding assays (Weichold et al., 2007). Indeed, the clinical trials described in the present invention demonstrate that the patients having active TB in these trials are “immunosuppressed” or “tolerant” with respect to at least some major Mtb antigens, although it is well known that, for instance, Ag85A and Ag85B are amongst the strongest immunogenic proteins of Mtb, the subjects did not have a response to these proteins. Thus, a therapeutic vaccine candidate should be capable of breaking this Mtb-induced tolerance on cell-mediated immunity.
Thus, the instant invention aims at providing therapeutic treatment of patients having active TB, which treatment should be effective yet comply with strict safety standards, and preferably should also be capable of being used in conjuction with drug therapy and preferably improve such drug therapy by shortening the duration thereof.